Role of the androgen receptor in prostate cancer

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1 ROSTATE DISEASE 26 Role of the androgen receptor in prostate cancer ALASTAIR D. LAMB AND DAVID E. NEAL Alastair D. Lamb, MB ChB, MRCS, hd, Clinical Lecturer and Honorary Specialist Registrar in Urology; David E. Neal, MB BS, MS, FMedSci, FSB, FRCS, FFM, rofessor of Surgical Oncology and Honorary Consultant Urological Surgeon, Cambridge Research Institute and University of Cambridge Department of Urology, Addenbrooke s Hospital GnRH Anterior pituitary LH Hypothalamus Testes ACTH >95% 5-alpha reductase Adrenal glands <5% T/AR DHT/AR Negative feedback Figure 1. Hypothalamo pituitary gonadal axis. Gonadotrophinreleasing hormone (GnRH) released from the hypothalamus induces release of gonadotrophins including luteinising hormone (LH) and adrenocorticotrophic hormone (ACTH) from the anterior pituitary gland. These in turn stimulate release of testosterone (T) from the testes (>95% of total T production) and from the adrenal gland (<5%). is converted to its more active metabolite dihydrotestosterone (DHT) by 5-alpha reductase. Both T and DHT can act as ligands to the androgen receptor (AR) Inhibition of the androgen receptor leads to regression of normal and malignant prostate tissue. The authors discuss therapeutic strategies for directly targeting the androgen receptor to help address the problem of castrate-resistant prostate cancer. THE HORMONAL BASIS OF ROSTATE GROWTH The hormonal basis of the prostate was first identified by John Hunter in He observed that rutting mammals such as male roe deer or moles have larger and more mucus-rich prostates during the rutting season. In 1876 elikan observed that the males in the Skopsty sect in Russia, who practised castration as a method of promoting sexual purity, had prostate glands that were the same size as those of children. 2 It was not until the 1940s, however, that the true significance of the androgen regulation of the prostate was discovered, when Charles Huggins reported that canine castration led to prostate shrinkage and reduced acid phosphatase secretion, while testosterone injection had the opposite effect. 3 He went on to show in eight patients with prostate cancer that orchidectomy and adrenalectomy removed circulating androgens. 4 Then in 1982 Redding and Schally demonstrated that a gonadotrophinreleasing hormone (GnRH) analogue, D-Trp6, effectively reduced normal prostate

2 ROSTATE DISEASE 27 size and tumour bulk in 344 rats. 5 This approach works by a negative feedback loop that is induced by overstimulation of the anterior pituitary gland (Figure 1). In current use, GnRH analogues are always initially given in conjunction with an androgen receptor antagonist that acts peripherally (such as bicalutamide) in order to protect against the initial androgen flare that occurs before the negative feedback mechanisms are fully active. Human AR NH 2 NTD DBD LBD DHT COOH HS- 90 NTD Flutamide Bicalutamide LBD DBD Enzalutamide rostate growth in the adult male depends on stimulation by circulating dihydrotestosterone (DHT), which is released predominantly by the testes in response to luteinising hormone (a gonadotrophin) from the anterior pituitary gland (Figure 1). The principal treatment options for organ-confined disease include prostatectomy, radiotherapy or active monitoring. For locally advanced tumours, hormone therapy is the mainstay of treatment. Indeed, hormone deprivation therapy is also the first option when surgical or radiotherapeutic options fail. 6 Coactivator LxxLL THE ANDROGEN RECETOR, ROSTATE CANCER AND RESISTANCE The androgen receptor is primarily responsible for mediating the effects of the hypothalamo pituitary gonadal axis on prostate growth and function. The androgen receptor is a steroid hormone receptor that is cytoplasmic in its unbound state, forming a circulating complex with heat-shock protein On androgen binding it undergoes a conformational change, allowing nuclear translocation and driving gene transcription (Figure 2). 7 The androgen receptor is a modular protein that features a central DNA-binding domain, with associated hinge region, ligand-binding domain and N-terminal transactivation domain (Figure 2). There are several splice variants of the androgen receptor and some have been shown to promote aggressive tumour activity. 8,9 Several coactivators that interact with different androgen receptor domains have Figure 2. Androgen receptor (AR) activation and mechanism for antiandrogen action. 7 The AR dissociates from heat-shock protein (HS)-90, binds dihydrotestosterone (DHT) and undergoes conformational change, nuclear translocation, DNA binding to androgen response elements, and coactivator recruitment, leading to transcriptional activity in the cell. With traditional antiandrogens some elements of this process can still take place. By contrast, when enzalutamide binds the AR, nuclear translocation is inefficient and DNA binding and coactivator recruitment are inhibited. NTD, N-terminal transactivation domain; DBD, DNA-binding domain; LBD, ligand-binding domain been implicated in increasing androgen receptor activation in therapy-resistant prostate cancer 10 and other research has focused on factors modulating the nuclear uptake/export of androgen receptor. 11 Inhibition of the androgen receptor leads to regression of normal and malignant prostate tissue. However, within approximately five years, 50 per cent of cancers become resistant and are termed androgeninsensitive prostate cancer, also known as hormone-refractory prostate cancer or castrate-resistant prostate cancer (CRC). 12 Several theories have been proposed to explain how the prostate cancer cell might replicate and grow in the absence of testosterone. These mechanisms can be divided according to their dependence on the androgen receptor. Androgen receptor-independent mechanisms include bypass pathways where prostate cancer cells grow by induction of alternative survival pathways and stem cell repopulation where androgen receptor-negative prostate cells grow out to form a non-androgen receptor-expressing tumour. Androgen receptor-dependent mechanisms include the so-called outlaw, promiscuous and hypersensitive pathways, which involve an androgen receptor that is activated by no ligand, other steroid ligands and tiny amounts of DHT, respectively (Figure 3). 13 TRENDS IN UROLOGY & MEN S HEALTH MAY/JUNE

3 ROSTATE DISEASE 28 (1) Outlaw pathway Grb2 SOS Ras Stem cell 13K MAK Akt AR AR (5) Stem cell repopulation TEN Another androgen-synthesis pathway that should be highlighted in view of recent discoveries involves the 5 per cent of testosterone that is released from the zona reticularis of the adrenal cortex (Figure 1). is synthesised directly here from cholesterol by the enzymes CY11A and CY This small additional source of testosterone in men becomes important when testosterone of testicular origin is suppressed by GnRH analogue-based therapy. 15,16 Activation of the androgen receptor has been shown to be a key promoter of tumorigenesis in carcinoma of the (2) romiscuous pathway Other steroids (3) Hypersensitive pathway prostate. 17,18 Therapeutic targeting of the androgen receptor with androgen blockade has been used effectively to modify growth and progression of prostate cancer. Of the five theories described above as mechanisms of castration resistance (Figure 3), three depend on continued androgen receptor activity. It is for this reason that prostate cancer has sometimes been grouped into three categories according to androgen receptor status and androgen dependency (Table 1). 19 The first of these categories describes the majority of primary prostate cancers. The second describes the outlaw, promiscuous 5-alpha DHT reductase Activation and proliferation (4) Bypass pathway Bcl-2 Bcl-xL Figure 3. Mechanisms of androgen resistance. 13 (1) The outlaw pathway. The androgen receptor (AR) is activated by phosphorylation from non-androgen sources such as Akt (protein kinase B) or the mitogen-activated protein kinase (MAK) pathway, producing a ligand-independent AR. (2) The promiscuous pathway. The AR is activated by non-androgen steroid hormones such as oestrogen or glucocorticoids. (3) The hypersensitive pathway. Increased levels of AR (usually by gene amplification) compensate for low levels of androgen or the small amount of residual testosterone is converted to more active forms. (4) The bypass pathway. AR-independent survival pathways are brought to bear. (5) The stem cell repopulation pathway. Androgen-independent cancer stem cells repopulate the tumour with androgen-independent cells and hypersensitive pathways outlined above, and the third describes mechanisms that are completely independent of androgen receptor involvement, which might lead to, for example, a small-cell or neuroendocrine tumour. It is likely that very few cancers are truly in the third category, with even the most advanced castrate-resistant tumours retaining androgen receptor expression. 20,21 STRATEGIES FOR TARGETING THE ANDROGEN RECETOR Androgen receptor function can be targeted therapeutically at several levels (Figures 1 and 2). The mainstay of medical prostate cancer treatment involves modulation of the hypothalamo pituitary axis with GnRH (also known as LHRH) analogues such as goserelin (Zoladex) or leuprorelin (rostap). In addition, oestrogens (stilboestrol, given with aspirin because of the elevated risk of venous thromboembolism) can also act at this level but are normally reserved for use once men become resistant to LHRH analogues. An LHRH antagonist has also been developed (degarelix, Firmagon) and early clinical trials demonstrate non-inferiority to LHRH agonists in terms of prostate-specific antigen (SA) progression-free survival. It remains to be seen whether degarelix improves overall survival. 22 The purpose of all these strategies is to suppress circulating testosterone. There are also strategies for directly targeting the androgen receptor. Traditional therapies include flutamide and its derivative bicalutamide, which has lower hepatoxicity and increased affinity for the androgen receptor. These were developed as androgen receptor antagonists, but have subsequently been found to show incomplete inhibition as a result of persistent androgen receptor coactivator activity (Figure 2). Ciproterone acetate is another androgen receptor antagonist traditionally used to cover for LHRH analogue flare, which also has some antigonadotrophic and steroid biosynthesis effects. 23,24 Enzalutamide is a more potent antagonist of the androgen

4 ROSTATE DISEASE 29 Androgen receptor Circulating androgen Type of prostate cancer status status Dependent Dependent Most primary prostate cancer Dependent Independent Outlaw, promiscuous, hypersensitive androgen receptor in CRC Independent Independent Bypass pathways in CRC, neuroendocrine tumours CRC, castrate-resistant prostate cancer. Table 1. Androgen receptor status in different forms of prostate cancer receptor, which disrupts nuclear androgen receptor translocation and DNA binding as well as preventing coactivator recruitment. 25 hase 2 trials showed antitumour activity with SA responses of 50 per cent in 50 per cent of patients, 26 and the interim analysis of the phase 3 trial (AFFIRM) has been published recently, with enzalutamide shown to be superior to placebo in terms of overall survival (18.4 versus 13.6 months), the primary endpoint, and in all secondary endpoints including SA response. 27 Abiraterone acetate works on the basis that the 5 per cent contribution of adrenal androgens to circulating DHT, which is not suppressed by LHRH analogues, is sufficient to drive androgen receptor activity. Abiraterone inhibits cytochrome KEY OINTS p450(cy)17, a key enzyme in the synthesis of adrenal androgen (Figure 1). It also inhibits intratumoral de novo biosynthesis of androgen. Early phase studies have confirmed the safety and tolerability of abiraterone when given with low-dose steroids to blunt the secondary adrenocorticotrophic hormone feedback loop. The phase 3 trial in docetaxel-treated CRC showed improved median overall survival of 3.9 months and, importantly, the survival benefit was similar when patients had received previous lines of CRC therapy. 16 CONCLUSION In conclusion, the androgen receptor plays a fundamental role in normal prostate cell growth and has been implicated in almost all forms of prostate cancer. It is likely that The androgen receptor is essential for normal prostate and prostate cancer cell growth Androgen receptor activity can be inhibited centrally by modulating GnRH activity (eg goserelin) or peripherally by receptor antagonists (eg bicalutamide) Androgen receptor transcriptional activity is almost always maintained, even in hormone-resistant cancer Novel agents such as abiraterone acetate (suppresses adrenal androgens) or enzalutamide (potent androgen receptor antagonist) have been shown to be effective in advanced prostate cancer persistent androgen receptor activity underpins much of lethal CRC, and promising targets are emerging to direct therapy in this regard. 28 The concern is that prostate cancer cells are versatile and can draw on a spectrum of pathways to bypass the need for conventional androgen receptor binding with testosterone to survive and divide. As we discover more about the androgen receptor and its fundamental transcriptional role in maintaining key cellular processes such as metabolism and cell cycle, fresh targets are being identified by which the most common non-cutaneous cancer in men can be selectively brought under control. Declaration of interests Alastair Lamb recently held a GlaxoSmithKline/Cambridge Biomedical Research Centre clinical research fellowship, and currently receives funds from the NIHR and University of Cambridge. David Neal receives funds from the University of Cambridge, NIHR, CRUK, MRC and DOH HTA. REFERENCES 1. Hunter J. Observations on certain parts of the animal oeconomy, edn 1. London: Bibliotheca Osteriana, 1786; elikan E. Gerichtlich-medicinische Untersuchungen uber Das Skopzenthum in Russland, nebst historischen Notizen. Giessen: Ricker, Huggins C, Clark J. Quantitative studies of prostatic secretion II: the effect of castration and of estrogen injection on the normal and on the hyperplastic prostate glands of dogs. J Exp Med 1940; 72: Huggins C. Effect of orchiectomy and irradiation on cancer of the prostate. Ann Surg 1942;115: Redding TW, Coy DH, Schally AV. rostate carcinoma tumor size in rats decreases after administration of antagonists of luteinizing hormone-releasing hormone. roc Natl Acad Sci USA 1982;79: Heidenreich A, Aus G, Bolla M, et al. EAU guidelines on prostate cancer. Eur Urol 2008;53: TRENDS IN UROLOGY & MEN S HEALTH MAY/JUNE

5 ROSTATE DISEASE Chen Y, Clegg NJ, Scher HI. Anti-androgens and androgen-depleting therapies in prostate cancer: new agents for an established target. Lancet Oncol 2009; 10: Zhang X, Morrissey C, Sun S, et al. Androgen receptor variants occur frequently in castration resistant prostate cancer metastases. LoS One 2011;6:e Watson SJ, Brown AJ, Holliday ND. Differential signaling by splice variants of the human free fatty acid receptor GR120. Mol harmacol 2012;81: Culig Z, Comuzzi B, Steiner H, et al. Expression and function of androgen receptor coactivators in prostate cancer. J Steroid Biochem Mol Biol 2004;92: Cutress ML, Whitaker HC, Mills IG, et al. Structural basis for the nuclear import of the human androgen receptor. J Cell Sci 2008;121: Schrijvers D. Androgen-independent prostate cancer. Recent Results Cancer Res 2007;175: ienta KJ, Smith DC. Advances in prostate cancer chemotherapy: a new era begins. CA Cancer J Clin 2005;55: Waterman MR, Keeney DS. Genes involved in androgen biosynthesis and the male phenotype. Horm Res 1992; 38: Titus MA, Schell MJ, Lih FB, et al. and dihydrotestosterone tissue levels in recurrent prostate cancer. Clin Cancer Res 2005;11: de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011;364: Nantermet V, Xu J, Yu Y, et al. Identification of genetic pathways activated by the androgen receptor during the induction of proliferation in the ventral prostate gland. J Biol Chem 2004;279: Abate-Shen C, Shen MM. Molecular genetics of prostate cancer. Genes Dev 2000;14: Gil J. Molecular basis for androgen independency in prostate cancer. Cancer Therapy 2006;4: Shen HC, Balk S. Development of androgen receptor antagonists with promising activity in castration-resistant prostate cancer. Cancer Cell 2009;15: Sharma NL, Massie CE, Ramos-Montoya A, et al. The androgen receptor induces a distinct transcriptional program in castration-resistant prostate cancer in man. Cancer Cell 2013; 23: Crawford ED, Tombal B, Miller K, et al. A phase III extension trial with a 1-arm crossover from leuprolide to degarelix: comparison of gonadotropin-releasing hormone agonist and antagonist effect on prostate cancer. J Urol 2011;186: Donald RA, Espiner EA, Cowles RJ, Fazackerley JE. The effect of cyproterone acetate on the plasma gonadotrophin response to gonadotrophin releasing hormone. Acta Endocrinol (Copenh) 1976;81: ham-huu-trung MT, de Smitter N, Bogyo A, Girard F. Effects of cyproterone acetate on adrenal steroidogenesis in vitro. Horm Res 1984;20: Tran C, Ouk S, Clegg NJ, et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science 2009;324: Scher HI, Beer TM, Higano CS, et al. Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1 2 study. Lancet 2010;375: Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012;367: Massie CE, Lynch A, Ramos-Montoya A, et al. The androgen receptor fuels prostate cancer by regulating central metabolism and biosynthesis. EMBO J 2011;30:

What s New in Advanced Disease (CRPC)?

What s New in Advanced Disease (castration resistant prostate cancer = CRC)? Matthew Rettig, MD Associate rofessor Department of Medicine Division of Hematology-Oncology Department of Urology Medical Director,